The investigators request support for an effort to find new classes of ligands that inhibit the gelation of sickle cell hemoglobin (HbS). They have already begun work on this project without external funding. The first step in their scheme relies on the preliminary screening of a library of known small molecule structures using a computational approach. The program DOCK utilizes stearic complementarity as a criterion to decide whether a chosen ligand might bind to a specific site on the surface of a protein. Instead of targeting the beta 85-88 binding site occupied by the mutant val-beta6 residue the applicants have chosen to try to disrupt the axial contacts within the HbS fiber by directing ligands to the vicinity of Glu-121, which lies directly in the inter-molecular interface within a single filament of the HbS fiber. Step two carries out more detailed, energy-based calculations on ligands suggested by DOCK. The investigators propose three experimental tests of ligands passing through their computational screen. First, to carry out a conventional anti-gelation assay on small HbS samples. Second, to measure whether the ligand has measurable binding to HbS. The latter step is necessary to avoid rejecting potentially useful compounds that are too small or too weakly binding to be seen in the anti-gelation assay. Third, to crystallize and determine the structures of any potentially useful complexes that form. Using DOCK the applicants have screened the Cambridge database of small molecule crystal structures, which contains ~90,000 entries. They have also done extensive energy-based computations on good candidates suggested by DOCK, and developed a list of about 100 compounds to try. Investigators are beginning anti-gelation assays on a subset of these. The requested support will provide the ability to: extend these calculations to databases comprising available and clinically valuable compounds; to purchase additional relevant software, and many more trial compounds than the applicants have been about to afford; to support development of the HbS binding assay; and to enable the proposed crystallographic studies.